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Triiodothyronine Stimulates Food Intake via the Hypothalamic Ventromedial Nucleus Independent of Changes in Energy Expenditure

Department of Metabolic Medicine (W.M.K., N.M.M., K.L.S., J.V.G., W.S.D., M.A.G., C.J.S., S.R.B.), Imperial College Faculty of Medicine at Hammersmith Campus, London W12 0NN, United Kingdom; Department of Physiology (I.P.C.), St. George’s Hospital Medical School, University of London, London SW17 0RE, United Kingdom; and Department of Mathematics (D.A.S.), Statistics Group, Imperial College, South Kensington Campus, London SW7 3AZ, United Kingdom

Address all correspondence and requests for reprints to: Professor S. R. Bloom, Department of Metabolic Medicine, Imperial College Faculty of Medicine at Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom. E-mail: s.bloom{at}imperial.ac.uk.

Increased food intake is characteristic of hyperthyroidism, although this is presumed to compensate for a state of negative energy balance. However, here we show that the thyroid hormone T₃ directly stimulates feeding at the level of the hypothalamus. Peripheral administration of T₃ doubled food intake in ad libitum-fed rats over 2 h and induced expression of the immediate early gene, early growth response-1, in the hypothalamic ventromedial nucleus (VMN), whereas maintaining plasma-free T₃ levels within the normal range. T₃-induced feeding occurred without altering energy expenditure or locomotion. Injection of T₃ directly into the VMN produced a 4-fold increase in food intake in the first hour. The majority of T₃ in the brain is reported to be produced by tissue-specific conversion of T₄ to T₃ by the enzyme type 2 iodothyronine deiodinase (D2). Hypothalamic D2 mRNA expression showed a diurnal variation, with a peak in the nocturnal feeding phase. Hypothalamic D2 mRNA levels also increased after a 12- and 24-h fast, suggesting that local production of T₃ may play a role in this T₃ feeding circuit. Thus, we propose a novel hypothalamic feeding circuit in which T₃, from the peripheral circulation or produced by local conversion, stimulates food intake via the VMN.

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